Method for the normalization of sexual response and amelioration of long term genital tissue degradation

ABSTRACT

The present invention provides, in one embodiment, a method of normalizing the timing of sexual response in a mammal comprising the administration of an amount of a central nervous system sexual response initiator in an amount sufficient to produce genital vasodilation but less than the amount required to produce effective vasocongestive arousal. The method is applicable not only to adjusting or normalizing the timing of sexual response in humans, but in the breeding of valuable commercial animals such as horses, cattle, sheep, swine and the like and domesticated pets such as dogs and cats. In an alternative embodiment, the present invention provides a method for the prophylactic treatment of long-term tissue degradation in the genital organs comprising the administration to a mammal of a central nervous system sexual response initiator in an amount sufficient to produce genital vasodilation but less than the amount required to produce effective vasocongestive arousal. The preferred central nervous system sexual response initiator is apomorphine or a pharmaceutically acceptable acid addition salt thereof.

TECHNICAL FIELD

The present application relates to pharmaceutical formulations and tomedical methods of treatment. More particularly, the present inventionconcerns the use of a compound which acts as a central nervous systemsexual response initiator for the normalization of the timing of sexualresponse in humans and for the prophylaxis or treatment of long-termdamage to genital organ.

BACKGROUND OF THE INVENTION

Proper sexual functioning in men and women depends upon a combination ofsteps including 1) establishment of the appropriate anticipatory mentalset (“desire”), 2) effective vasocongestive arousal (an erection in themale sufficient for vaginal penetration and, in the female, clitoralerection, vaginal engorgement and lubrication), and 3) orgasm. Thetiming of these steps between partners engaging in sexual relations ismediated by one or more of several compounds which act in neurologicalpathways in the mesencephalon or mid-brain. These pathways include thosetermed the serotonergic, dopaminergic, oxytocinergic, and nitroxidergicmid-brain pathways. Timing of the various aspects or parameters ofsexual response between partners engaging in sex is important and oftenmis-matched due to psychological, or sometimes biogenic, dysfunction inone or both of the partners. Even in sex partners having sexualresponses deemed to fall within the norm, there is a frequent mis-matchof the timing of response.

Orgasm in the male includes the sensation of emission followed byejaculation. The sensation of emission is one of ejaculatoryinevitability and is mediated by contractions of the prostate, seminalvesicles, and urethra. Orgasm in the female is accompanied bycontractions of the muscles that line the wall of the outer third of thevagina. In both sexes, generalized muscular tension, perinealcontractions and involuntary pelvic thrusting usually occur. Orgasm isfollowed by resolution, a sense of general relaxation, well-being, andmuscular relaxation. During this phase men are physiologicallyrefractory to further erection and orgasm for a variable period of time.In contrast, women may be able to respond to additional stimulationalmost immediately.

Sexual response is mediated by a balanced interplay between thesympathetic and parasympathetic nervous systems. Vasocongestion, orerectile tumescence, is largely mediated by parasympathetic(cholinergic) outflow, whereas orgasm is predominantly sympathetic(adrenergic). Ejaculation is almost entirely sympathetic, whereasemission involves a much more finely balanced combination of sympatheticand parasympathetic stimulation.

Normal biological response in humans results in ejaculation typicallywithin about two minutes or more following vaginal penetration. Mostwomen are unable to reach orgasm within this short period of time, onecause of the problem of inappropriate timing of sexual response betweensexual partners, even when the sexual responses of both are withinphysiological norms. In the case of the sexual dysfunction in malesknown as premature ejaculation, the problem is further exacerbated.

Premature ejaculation in males may have either a psychogenic or biogenicorigin in a particular individual, and various treatment methods havebeen suggested. These include counseling and techniques for learningcontrol of ejaculation and the use of serotonin re-uptake inhibitorssuch as fluoxetine hydrochloride (Prozac®) and sertraline hydrochloride(Zoloft®) to delay the onset of the sensation of emission.

The problem of inappropriate timing of sexual response is not limited tothe human species, but occurs also in lower mammals as well, forexample, in the breeding of valuable commercial animals such as horses,cattle, sheep, swine and the like and domesticated pets such as dogs andcats.

United States Patent (Ser. No. 08/546,498) discloses a method ofameliorating erectile dysfunction in a male patient by administration ofapomorphine or a salt thereof in an amount sufficient to induce anerection adequate for vaginal penetration, but less than that whichinduces nausea.

The need remains, however, for the development of effective means tonormalize the timing of sexual response in mammals, including humansand, in particular, in those cases involving premature ejaculation inhuman males.

In addition, there is a need for agents for the prophylaxis andtreatment of long-term degradative effects or damage to genital organtissues in mammals.

BRIEF DESCRIPTION OF THE DRAWING FIGURE

FIG. 1 is a linear plot of the mean plasma concentrations of apomorphinefollowing the administration of sub-cutaneous and sublingual doses ofapomorphine.

SUMMARY OF THE INVENTION

It has been found, in accordance with one embodiment of the presentinvention that the acute administration of an agent which acts uponmid-brain dopaminergic, serotonergic, oxytocinergic or nitroxidergicpathways to initiate mammalian sexual response in an amount which isinsufficient to produce effective vasocongestive arousal, but issufficient to produce increased genital vasodilation, acts to normalizethe timing of sexual response between sexual partners.

In another embodiment, the present invention provides a method ofameliorating long-term genital organ tissue damage comprising thechronic administration of a mammalian central nervous system sexualresponse initiator in an amount less than that required to produce avasocongestive arousal in said mammal, but sufficient to causevasodilation in the genitalia.

DETAILED DESCRIPTION

In the first embodiment of the invention, a central nervous systemsexual response initiator is administered to a mammal in an acute doseto one or both partners in the period just prior to sexual intercourse,preferably in a dose insufficient to cause effective vasocongestivearousal, but sufficient to increase genital vasodilation to aid in thenormalization of the timing of sexual response between the sexualpartners. The drug is administered during the period between about twoto about one-hundred-twenty minutes prior to sexual relations,preferably in the period between about two and sixty minutes prior tosexual relations.

In the case where the male suffers from the sexual dysfunction termedsexual arousal disorder (inability to attain the psychic readiness,and/or sustain an erection satisfactory for normal coitus) or thecondition known as premature ejaculation, the drug is administered tothe male partner. Where the female suffers sexual arousal disorder(persistent or recurrent failure to attain the psychic readiness and/ormaintain the lubrication-swelling response), the drug is administered tothe female partner. In the case of both the male and female partners,the drug may also be co-administered with a low dose of androgen topotentiate the effect of the mid-brain pathway mediator drug.

By “androgen” is meant testosterone, dihydrotestosterone, anddehydroepiandrostenedione, either in their free base forms or in theform of a salt or pro-drug.

The terms “acute dose” or “acute administration” of the drug mean thescheduled administration of the drug to the patient on an as-neededbasis.

The term “central nervous system sexual response initiator” denotes acompound which acts in any of the dopaminergic, serotonergic,oxytocinergic or nitroxidergic mammalian mid-brain pathways to initiatea sexual response.

Dopaminergic pathway initiators include apomorphine, bromocriptine,lisuride, methergoline, pergolide, piribidil, and quinpirole.

Serotonergic pathway initiators include serotonin receptor agonists suchas 1-(2,5-dimethoxy-4-iodophenyl)-1-aminopropane, 5-methoxytryptamine,α-methyl-5-hydroxytryptamine, 2-methyl-5-hydroxytryptamine,N-acetyl-5-hydroxytryptamine buspirone, and sumatriptin.

Oxytocinergic pathway initiators include oxytocin analogues such asisotocin, carbetocin, Lys-conopressin, deaminooxytocin, mesotocin,antocin, glimitocin, aspargitocin, valitocin, asvatocin, phasvatocin,and seritocin.

The preferred central nervous system sexual response initiator for usein the methods of the present invention is apomorphine or one of itssalts or pro-drug forms.

Apomorphine,(R)-5,6,6a,7-tetrahydro-6-methyl-(4H)-dibenzo[de,g]quinoline-10,11-diol,is a derivative of morphine obtained by treatment of the latter withconcentrated hydrochloric acid (L. Small, et al., J. Org. Chem., 5: 334(1940)) or by heating morphine with zinc chloride (Mayer, Ber., 4: 171(1871)). The compound has the chemical structure:

and possesses a chiral center at position 6a. The total synthesis of theracemic mixture is reported by J. L. Neumeyer, et al., J. Pharm. Sci.,59:1850 (1970) and the synthesis of the separate enantiomers by V. J.Ram and J. L. Neumeyer, J. Org. Chem., 46: 2830 (1981).

The compound possesses a basic nitrogen atom at position 6 and is thuscapable of existing in the free base form as well as acid addition saltforms. The compound may be administered as the free base or in the formof one of its pharmaceutically acceptable salts or pro-drug derivatives.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, S. M. Berge, etal. describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977). The salts are prepared in situduring the final isolation and purification of the compounds of theinvention, or separately by reacting the free base function with asuitable organic acid. Examples of pharmaceutically acceptable, nontoxicacid addition salts are salts of an amino group formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid or malonic acid or by using other methods used in the art such asion exchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

The term “pro-drug” refers to compounds that are rapidly transformed invivo to yield the parent compound, as for example, by hydrolysis inblood. T. Higuchi and V. Stella provide a thorough discussion of thepro-drug concept in “Pro-drugs as Novel Delivery Systems”, Vol. 14 ofthe A.C.S. Symposium Series, American Chemical Society (1975). Examplesof esters useful as pro-drugs for compounds containing carboxyl groupsmay be found on pages 14-21 of “Bioreversible Carriers in Drug Design:Theory and Application,” edited by E. B. Roche, Pergamon Press (1987).

The term “pro-drug ester group” refers to any of several ester-forminggroups that are hydrolyzed under physiological conditions. Examples ofpro-drug ester groups include pivoyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, as well as other such groupsknown in the art.

As used herein, the term “pharmaceutically acceptable ester” refers toesters which hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters includes formates, acetates, propionates,butryates, acrylates and ethylsuccinates.

By the term “normalizing” or “normalization” of the timing of sexualresponse in a human is meant adjusting the time of onset, duration, andlikelihood of a sexual response so that these parameters tend toward thenormal response for a human under the given circumstances. Normalizationof sexual response can include delay of onset of the sensation ofemission, delay of ejaculation, and prolongation of the duration oferection in the male and, in the female, increase in the likelihood ofclitoral erection, swelling and lubrication.

The term “premature ejaculation” in the male is meant the sexualdysfunction characterized by persistent or recurrent ejaculation before,upon, or shortly after vaginal penetration. More generally, the term canbe defined as ejaculation occurring before the individual wishes.

The term “vasocongestive arousal” means, in the male, tumescent penileerection, but insufficient for vaginal penetration and, in the female,clitoral erection and engorgement and swelling of the vagina and labia.The term “effective vasocongestive arousal” means, in the male, anerection sufficient for vaginal penetration.

The following study illustrates the use of apomorphine, a representativedrug of the class of compounds contemplated by the present invention,for normalizing the timing of sexual response by administration of thedrug to males to extend the duration of erection.

A multi-center, double-blind, randomized, placebo-controlled,three-armed study was conducted on 370 patients diagnosed with maleerectile dysfunction with no major organic component. For each sequence,patients received placebo in one of the treatment periods, and a dose (2mg, 4 mg, or 6 mg) of apomorphine in the other treatment period. Thisarrangement resulted in approximately one-third of the patientsreceiving one of the three apomorphine doses.

During treatment periods of the study, patients and their sexualpartners were instructed to attempt intercourse a minimum of twiceweekly. Each time the study drug was taken, a questionnaire wascompleted by the patient and by the partner and mailed to the studysponsor. The questionnaire recorded the date and time the study drug wastaken, an evaluation of the erection, whether or not sexual intercoursehad occurred, and satisfaction associated with each attempt. The patientalso completed a diary which recorded the latency and duration oferections associated with the use of the study drug and antiemetic andconcomitant medication usage and any adverse effects. If an erectionoccurred after administration to the patient of the study drug, theduration of erection and time-to-erection were recorded in the patientdiary. The data from these studies are presented in Tables 1-4.

Table 1 shows the mean durations in minutes of erections for patientsreceiving a dose (2 mg, 4 mg, or 6 mg) of apomorphine versus placebo ineach case for all attempts. If the attempt failed to produce anerection, a value of zero minutes was used in the statistical analysis.The data in Table 1 indicate dose-dependent, statistically significantdifferences in the mean durations of erections between drug and placebo,with the mean values being lowered by overall by inclusion of zero valuedata from attempts which did not result in an erection.

Table 2 shows the data for only those attempts which did result in anerection. The data in Table 2 also indicate a dose-dependent,statistically significant difference of duration of erection, with adifference of almost 5 minutes between patients taking the 6 mg dose andthose receiving placebo.

Table 3 presents the median time to erection for patients involved inthe study and shows data for all attempts. In those cases where noerection was achieved, a value of 60 minutes time-to-erection was usedin the statistical analysis. The data in Table 3 show differences inlatency periods between patients receiving apomorphine and thosereceiving placebo, but the differences probably reflect the inclusion inthe data of 60 minute values for those cases in which no erection wasachieved.

Table 4 shows the data only for patients where an attempt was successfulin achieving an erection. The data in Table 4 show that there was nostatistically significant difference in the median time-to-erectionbetween patients receiving the drug and those receiving placebo, with amedian time-to-erection of about 12 minutes.

One conclusion to be drawn from the data presented in Tables 1-4 is thatadministration of apomorphine at the doses tested did not shorten orprolong the time of onset of erection despite effects on the duration oferection when compared to placebo, but resulted in a significantincrease in the duration of erection. Keeping in mind the generallylonger time typically required for females to reach orgasm in the cycleof sexual response, administration of the drug to the male partnerserves to normalize the timing of sexual response between coitalpartners.

The data in Tables 3 and 4 are instructive in another light. The mediantime-to-erection in patients receiving the study drug at all dosestested was approximately 12 minutes. However, a pharmacokineticevaluation of apomorphine, TABLE 1 Duration of Erection Results ofStatistical Analysis of Average Durations Based on All Attempts NumberDifference Standard of Mean in Means Error of P- Study Arm TreatmentPatients (Minutes) (Minutes) the Mean Value Apomorphine 6 mg Drug 1118.393 5.138 0.883 <0.001¹ Placebo 111 3.255 Apomorphine 4 mg Drug 1296.903 3.578 0.637 <0.001¹ Placebo 129 3.325 Apomorphine 2 mg Drug 1355.020 1.936 0.534 <0.001¹ Placebo 135 3.084¹Statistically significant at P = 0.001.Notes:An “attempt” is defined to be the taking of the study drug andcompletion by the patient of the appropriate efficacy question on thepatent questionnaire.Analysis was done on average duration of erection for each patientduring each period. For attempts which did not result in an erection, anduration of zero minutes was used in the statistical analysis.All means, standard errors and P-values are from an ANOVA model, witheffects for treatment, period, sequence, and patient within sequence.

TABLE 2 Duration of Erection Results of Statistical Analysis of AverageDurations Based on All Attempts Where Erection Was Achieved TreatmentNumber Difference Difference Treatment of Mean in Means Standard StudyArm Regimen Patients (Minutes) (Minutes) Error Apomorphine Drug 70 13.964.925 0.959 6 mg Placebo 70 9.030 Apomorphine Drug 86 12.49 3.458 0.8694 mg Placebo 86 9.028 Apomorphine Drug 83 10.82 1.811 0.978 2 mg Placebo83 9.012Notes:An “attempt” is defined to be the taking of the study drug andcompletion by the patient of the appropriate efficacy question on thepatent questionnaire.Analysis was done on average duration of erection for each patientduring each period. Attempts which did not result in an erection werenot used in the statistical analysis.All means, standard errors are from an ANOVA model with effects fortreatment, period, sequence, and patient within sequence.

TABLE 3 Time to Erection Kaplan-Meier Estimation of Median Time toErection Based on All Attempts 95% Treatment Number of Mean ConfidenceStudy Arm Regimen Patients (Minutes) Interval Apomorphine 6 mg Drug 11131.33 26.50-36.67 Placebo 111 47.50 43.75-52.86 Apomorphine 4 mg Drug131 36.00 32.50-42.27 Placebo 131 47.78 42.73-50.83 Apomorphine 2 mgDrug 135 42.17 35.33-48.25 Placebo 135 50.00 44.86-54.38Notes:An “attempt” is defined to be the taking of the study drug andcompletion by the patient of the appropriate efficacy question on thepatent questionnaire.Analysis was done on average time until erection for each patient duringeach period. For attempts which did not result in an erection, a timeuntil erection of 60 minutes was used.

TABLE 4 Time to Erection Kaplan-Meier Estimation of Median Time toErection Based on All Attempts When Erection Occurred 95% TreatmentNumber of Treatment Confidence Study Arm Regimen Patients Means IntervalApomorphine 6 mg Drug 96 12.82 10.00-16.67 Placebo 82 11.67 10.00-14.00Apomorphine 4 mg Drug 110 12.61 10.00-16.00 Placebo 94 12.75 10.00-15.00Apomorphine 2 mg Drug 109 11.33 10.00-15.00 Placebo 92 12.42 10.30-15.00Notes:An “attempt” is defined to be the taking of the study drug andcompletion by the patient of the appropriate efficacy question on thepatent questionnaire.Analysis was done on average time until erection for each patient duringeach period.Analysis is based on the first eight attempts.illustrated in the graph depicted in FIG. 1, shows that the timerequired to reach maximum blood serum levels following subcutaneousdelivery of apomorphine is approximately 15 minutes. However, as shownby the pharmacokinetic curves in FIG. 1, the maximum plasmaconcentrations following sub-lingual administration (the formulationused in the studies presented in Tables 1-4), was not reached untilabout 60 minutes following administration.

The data presented in Tables 3 and 4 show that the mediantime-to-erection is about 12 minutes, one-fifth the time required toreach maximum plasma concentrations following buccal administration.Since erections were observed in patients who had experienced difficultyachieving an erection in the absence of the drug, the data thus show atherapeutic effect beginning at 12 minutes following buccaladministration. As shown by examination of FIG. 1, at that point intime, the drug has reached approximately one-fifth to one-fourth maximumblood serum levels, indicating that it is producing the desired effectat lower doses than initially believed necessary. In the period betweenadministration of apomorphine and about 20 minutes followingadministration, the plasma concentration curves for all three dosestested (2 mg, 4 mg, and 6 mg) show similar profiles and interpolation ofthe data indicate that plasma apomorphine levels less than about 0.25ng/mL are sufficient to cause a therapeutic effect. Production of plasmaapomorphine concentrations generally ranging between about 0.02 ng/mLand 0.25 ng/mL are preferred for the method of this embodiment of theinvention.

Thus the administration of a dose of apomorphine lower than thatrequired for effective congestive arousal, but sufficient to increasegenital blood flow is effective in extending the duration of erectionand aids in normalizing the timing of sexual responses between thepartners in intercourse.

Preferably, the dose administered to the patient in this embodiment ofthe invention is generally sufficient to produce mean plasma levels lessthan about 0.25 ng/mL, preferably in the range of about 0.02 ng/mL toabout 0.25 ng/mL. These serum levels translate into doses generallyranging between about 0.02 mg to about 4 mg per dose, depending upon theformulation delivery system. In this embodiment of the invention, themode of delivery of the drug is by acute administration; that is, in adose administered on an as-needed basis in the time period immediatelyprior to sexual intercourse. The drug is preferably administered in aformulation which rapidly delivers the drug to the system and any methodknown to the practitioner of the pharmaceutical formulation arts whichaccomplishes this means may be used. For example, the drug may berapidly delivered to the system by means of a liquid formulation appliedsub-lingually; by a tablet, lozenge, or lollipop held in the mouth andabsorbed buccally; by means of a suppository formulation administeredintravaginally or rectally; by a powder, gel, or suspension, or anintra-nasal spray formulation.

The drug may also be administered in a sterile parenteral formulation bysub-cutaneous or intramuscular route, although sub-lingual, buccal,intra-nasal, and suppository formulations are preferred because of theirgreater ease of administration and the resulting greater potential forpatient acceptance.

Depending upon the T_(max) for a particular formulation, the drug isadministered in the time period immediately prior to sexual intercourse,generally during the period between about 2 minutes and 120 minutesprior to sexual relations, preferably during the period between about 2minutes and about 60 minutes prior to sexual relations.

In cases where the male sex partner suffers from sexual arousaldisorder, or premature ejaculation, the drug is administered to themale, optionally with the co-administration of a low dose of androgen.In those instances where the female sex partner suffers from sexualarousal disorder, the drug is administered to the female, optionallywith co-administration of a low dose of androgen.

By “co-administration” is meant 1) the administration of an androgen ina separate dosage form prior to administration of apomorphine, takinginto account the particular pharmacokinetic profile of the androgen, and2) the concomitant administration of the androgen and apomorphine inthose cases where the pharmacokinetic profiles of the two drugs aresimilar. In concomitant administration of apomorphine and an androgen,the two drugs may be administered in a single dosage form, or may beadministered at the same time in separate dosage forms.

In studies with female rats, response to apomorphine was observed whentreated with low doses of testosterone. Animals treated with acombination of apomorphine and testosterone exhibited lordosis, genitalgrooming and other behaviors typically associated with sexual arousal.Suitable androgens for use in this embodiment of the invention includetestosterone, dihydrotestosterone, and dehydroepiandrostenedione withtestosterone being particularly preferred. When co-administration of anandrogen is utilized in this method of the invention, the androgen isgiven is doses sufficient to produce plasma concentrations of about 1nmol/L to 200 nmol/L As would be apparent to a person of ordinary skillin the art, it is reasonable to use the rat as a model for the affectedvascular systems discussed herein such as, for example, the pudendal andpenile vasculature, and to extend such studies to appropriate dosagesand therapies for other subjects such as higher mammals and humans. Asevidenced by Mordenti, “Man versus Beast: Pharmacokinetic Scaling inMammals,” J. Pharm. Sci., 75: 1028-1040 (1986) and similar articles,dosage forms for animals such as, for example, rats can be and arewidely used directly to establish dosage levels in therapeuticapplications in higher mammals, including humans

One of the present inventors contributed to the development of abioassay of erectile function in a rat model at leastas early as 1991(J. P. W. Heaton, et al., J. Urol., 145: 1099-1102 (1991)), and alsohelped to demonstrate in comparative tests of erectile function inhumans and rats, that the narrow effective dose window for an orallyadministered drug, apomorphine, is almost identical when suitablyadjusted for the differences in body weight as taught by Mordenti, citedabove (J. P. W. Heaton, et al., Urology, 45: 200-206 (1995)).

In an alternative embodiment of the present invention, a central nervoussystem sexual response initiator is administered chronically in a lowmaintenance dose to prevent, ameliorate, or reverse the damaging effectsto the genital organs of extended periods of vasoconstriction. In thisembodiment, the drug is administered on a repetitive or recurringscheduled basis over a long period of time, for example once daily, onceweekly, or by a depot formulation such as a transdermal patch orbiodegradeable intramuscular depot formulation.

The terms “chronic administration,” or “maintenance dose” of a drugrefer to the scheduled repetitive and regular administration of a drugto the patient over a long term.

The arteries in a normal flaccid penis and the unenlarged clitoris andlabia are constricted. As a result, typical oxygen concentrations insuch tissues are closer to venous rather than arterial oxygen levels.Periodic vasodilation of the penis and clitoris increase oxygen levelsin these tissues. The higher oxygen levels supplied to tissue in thepenis and clitoris, as well as vasodilation itself, shut down adversemetabolic processes such as TGF-β production and vascular wallremodeling which result in long term tissue damage. Thus under normalconditions, for example, a man has three to five erections per night inthe body's self-regulating mechanism for vasodilating and oxygenatingpenile tissues.

For the purposes of this embodiment, it is not necessary that the drugbe administered in an amount necessary to produce effectivevasocongestive arousal, that is, in the male an erection sufficient forvaginal penetration. Typically a lower dose, sufficient for inducingvasodilation and increased blood flow to the genitalia is sufficient,generally daily doses sufficient to produce mean plasma concentrationsof apomorphine of less than about 0.2 ng/mL, preferably in the range ofabout 0.02 ng/mL to about 0.2 ng/mL.

The maintenance of these low levels of serum concentration of the drugresult in tumescence which is insufficient for intercourse, but producesufficient vasodilation of the genital organs to combat the deleteriouseffects of restricted blood flow to the organs over time. Since theobject of this embodiment of the invention is to obtain a low,steady-state blood serum level of the drug, the drug formulation neednot be one which delivers the drug rapidly to the system, and typicalformulations known in the art such as tablets, pills, lozenges, syrups,elixirs, suspensions and the like, such as those described below may beemployed.

Pharmaceutical Formulations

Pharmaceutical compositions suitable for administration of the drug ofthe present invention comprise a therapeutically effective amount of thedrug formulated together with one or more pharmaceutically acceptablecarriers. As used herein, the term “pharmaceutically acceptable carrier”means a non-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as cocoabutter and suppository waxes; oils such as peanut oil, cottonseed oil;safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols;such a propylene glycol; esters such as ethyl oleate and ethyl laurate;agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally, intravaginally,topically (as by powders, ointments, or drops), bucally, or as an oralor nasal spray.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents. Injectable preparations, for example, sterile injectable aqueousor oleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides) Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues. Compositions forrectal or vaginal administration are preferably suppositories which canbe prepared by mixing the compounds of this invention with suitablenon-irritating excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax which are solid at ambient temperature butliquid at body temperature and therefore melt in the rectum or vaginalcavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules using such excipients as lactose or milk sugar as wellas high molecular weight polyethylene glycols and the like. The soliddosage forms of tablets, dragees, capsules, pills, and granules can beprepared with coatings and shells such as enteric coatings and othercoatings well known in the pharmaceutical formulating art. They mayoptionally contain opacifying agents and can also be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of embedding compositions which can be used include polymericsubstances and waxes.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The active compounds can also be in micro-encapsulated formwith one or more excipients as noted above. The solid dosage forms oftablets, dragees, capsules, pills, and granules can be prepared withcoatings and shells such as enteric coatings, release controllingcoatings and other coatings well known in the pharmaceutical formulatingart. In such solid dosage forms the active compound may be admixed withat least one inert diluent such as sucrose, lactose or starch. Suchdosage forms may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g., tableting lubricants andother tableting aids such a magnesium stearate and microcrystallinecellulose. In the case of capsules, tablets and pills, the dosage formsmay also comprise buffering agents. They may optionally containopacifying agents and can also be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain part of theintestinal tract, optionally, in a delayed manner. Examples of embeddingcompositions which can be used include polymeric substances and waxes.Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, ear drops, eye ointments, powders and solutionsare also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof. Powders and sprays cancontain, in addition to the compounds of this invention, excipients suchas lactose, talc, silicic acid, aluminum hydroxide, calcium silicatesand polyamide powder, or mixtures of these substances. Sprays canadditionally contain customary propellants such aschlorofluorohydrocarbons.

Transdermal patches have the added advantage of providing controlleddelivery of a compound to the body. Such dosage forms can be made bydissolving or dispensing the compound in the proper medium. Absorptionenhancers can also be used to increase the flux of the compound acrossthe skin. The rate can be controlled by either providing a ratecontrolling membrane or by dispersing the compound in a polymer matrixor gel.

While there have been described and illustrated preferred embodiments ofthe present invention, one of ordinary skill in the art to which theinvention pertains will recognize that various modifications may be madewithout departing from the scope of the invention as it is defined bythe appended claims.

1. A method of normalizing the timing of sexual response in a mammalcomprising the administration of an amount of a central nervous systemsexual response initiator in an amount sufficient to produce genitalvasodilation but less than the amount required to produce effectivevasocongestive arousal in said human.
 2. A method in accordance withclaim 1 comprising administering said central nervous system sexualresponse initiator to said mammal during a period of between about twoto about one-hundred-twenty minutes immediately prior to coitus.
 3. Amethod in accordance with claim 1 wherein said central nervous systemsexual response initiator is selected from such agents which act uponone or more dopaminergic, serotonergic, oxytocinergic or nitroxidergicmid-brain pathways to initiate a sexual response.
 4. A method inaccordance with claim 3 wherein said central nervous system initiator isa compound acting upon the dopaminergic mid-brain pathway selected fromthe group consisting of apomorphine, bromocriptine, lisuride,methergoline, pergolide, piribidil, and quinpirole or a pharmaceuticallyacceptable salt or pro-drug thereof.
 5. A method in accordance withclaim 3 wherein said central nervous system initiator is a compoundacting upon the serotonergic mid-brain pathway selected from the groupconsisting of 1-(2,5-dimethoxy-4-iodophenyl)-1-aminopropane,5-methoxytryptamine, α-methyl-5-hydroxytryptamine,2-methyl-5-hydroxytryptamine, N-acetyl-5-hydroxytryptamine, buspirone,and sumatriptin or a pharmaceutically acceptable salt or pro-drugthereof.
 6. A method in accordance with claim 3 wherein said centralnervous system initiator is a compound acting upon the oxytocinergicmid-brain pathway selected from the group consisting of isotocin,carbetocin, Lys-conopressin, deaminooxytocin, mesotocin, antocin,glumitocin, aspargitocin, valitocin, asvatocin, phasvatocin, andseritocin.
 7. A method of normalizing the timing of sexual response in amammal comprising the administration of an amount of apomorphine or apharmaceutically acceptable salt or pro-drug thereof in an amountsufficient to produce genital vasodilation but less than that requiredto produce effective vasocongestive arousal in said human.
 8. The methodaccording to claim 7 wherein said apomorphine or pharmaceuticallyacceptable salt or pro-drug thereof is administered to said mammalduring a period of between about two to about one-hundred-twenty minutesimmediately prior to coitus.
 9. The method according to claim 7 whereinsaid apomorphine or pharmaceutically acceptable salt or pro-drug thereofis administered to said mammal during a period of between about two toabout sixty minutes immediately prior to coitus.
 10. The methodaccording to claim 7 wherein said apomorphine or pharmaceuticallyacceptable salt or pro-drug thereof is administered to said mammal in anamount sufficient to produce plasma apomorphine concentrations less thanabout 0.25 ng/mL.
 11. The method according to claim 7 wherein saidapomorphine or pharmaceutically acceptable salt, ester or pro-drugthereof is administered to said mammal in an amount sufficient toproduce plasma apomorphine concentrations of a level ranging betweenabout 0.02 ng/mL to about 0.25 ng/mL.
 12. The method according to claim7 further comprising co-administration of an androgen.
 13. The methodaccording to claim 12 wherein said androgen is selected from the groupconsisting of testosterone, dihydrotestosterone, anddehydroepiandrostenedione or a pharmaceutically acceptable salt orpro-drug thereof.
 14. The method according to claim 13 wherein saidandrogen is testosterone or a pharmaceutically acceptable salt orpro-drug thereof.
 15. A method of prolonging vasocongestive arousal in amammal comprising administering to said mammal an amount of apomorphineor a pharmaceutically acceptable salt or pro-drug thereof in an amountsufficient to produce plasma concentrations less than about 0.25 ng/mL.16. The method according to claim 15 wherein said apomorphine orpharmaceutically acceptable salt or pro-drug thereof is administered tosaid human in an amount sufficient to produce plasma apomorphineconcentrations of a level ranging between about 0.02 ng/mL to about 0.25ng/mL.
 17. The method according to claim 7 wherein said mammal is ahuman male.
 18. The method according to claim 17 wherein said human malesuffers from sexual arousal disorder.
 19. The method according to claim17 wherein said human male suffers from premature ejaculation.
 20. Themethod according to claim 18 wherein said apomorphine orpharmaceutically acceptable salt thereof is administered to said humanmale in an amount sufficient to produce plasma apomorphineconcentrations less than about 0.25 ng/mL.
 21. The method according toclaim 18 wherein said apomorphine or pharmaceutically acceptable salt orpro-drug thereof is administered to said human in an amount sufficientto produce plasma apomorphine concentrations of a level ranging betweenabout 0.02 ng/mL to about 0.25 ng/mL.
 22. The method according to claim19 wherein said apomorphine or pharmaceutically acceptable salt thereofis administered to said human male in an amount sufficient to produceplasma apomorphine concentrations less than about 0.25 ng/mL.
 23. Themethod according to claim 19 wherein said apomorphine orpharmaceutically acceptable salt or pro-drug thereof is administered tosaid human in an amount sufficient to produce plasma apomorphineconcentrations of a level ranging between about 0.02 ng/mL to about 0.25ng/mL.
 24. The method according to claim 7 wherein said mammal is ahuman female.
 25. The method according to claim 24 wherein saidapomorphine or pharmaceutically acceptable salt thereof is administeredto said human female in an amount sufficient to produce plasmaapomorphine concentrations less than about 0.25 ng/mL.
 26. The methodaccording to claim 25 wherein said apomorphine or pharmaceuticallyacceptable salt thereof is administered to said human female in anamount sufficient to produce plasma apomorphine concentrations of alevel ranging between about 0.02 ng/mL to about 0.25 ng/mL.
 27. Themethod according to claim 23 wherein said human female suffers fromsexual arousal disorder.
 28. The method according to claim 27 whereinsaid apomorphine or pharmaceutically acceptable salt thereof isadministered to said human female in an amount sufficient to produceplasma apomorphine concentrations less than about 0.25 ng/mL.
 29. Themethod according to claim 28 wherein said apomorphine orpharmaceutically acceptable salt or pro-drug thereof is administered tosaid human female in an amount sufficient to produce plasma apomorphineconcentrations of a level ranging between about 0.02 ng/mL to about 0.25ng/mL.
 30. A method of prophylaxis or amelioration of long-term genitalorgan tissue damage in a mammal comprising the administration of amammalian central nervous system sexual response initiator in an amountsufficient to cause vasodilation in the genitalia but less than thatrequired to produce an effective vasocongestive arousal in said mammal.31. A method in accordance with claim 30 wherein said central nervoussystem initiator is selected from compounds which act upon one or moremammalian dopaminergic, serotonergic, oxytocinergic or nitroxidergicmid-brain pathways to initiate a sexual response.
 32. A method inaccordance with claim 31 wherein said central nervous system initiatoris a compound acting upon the dopaminergic mid-brain pathway selectedfrom the group consisting of apomorphine, bromocriptine, lisuride,methergoline, pergolide, piribidil, and quinpirole or a pharmaceuticallyacceptable salt or pro-drug thereof.
 33. A method in accordance withclaim 31 wherein said central nervous system initiator is a compoundacting upon the serotonergic mid-brain pathway selected from the groupconsisting of 1-(2,5-dimethoxy-4-iodophenyl)-1-aminopropane,5-methoxytryptamine, α-methyl-5-hydroxytryptamine,2-methyl-5-hydroxytryptamine, N-acetyl-5-hydroxytryptamine, buspirone,and sumatriptin or a pharmaceutically acceptable salt or pro-drugthereof.
 34. A method in accordance with claim 31 wherein said centralnervous system initiator is a compound acting upon the oxytocinergicmid-brain pathway selected from the group consisting of isotocin,carbetocin, Lys-conopressin, deaminooxytocin, mesotocin, antocin,glumitocin, aspargitocin, valitocin, asvatocin, phasvatocin, andseritocin.
 35. A method of ameliorating long-term genital organ tissuedamage in a mammal comprising the chronic administration of apomorphineor a pharmaceutically acceptable salt thereof in an amount less thanthat required to produce effective vasocongestive arousal in saidmammal, but sufficient to cause vasodilation in the genitalia.
 36. Themethod according to claim 35 wherein said apomorphine orpharmaceutically acceptable salt thereof is administered to said humanin an amount sufficient to produce plasma concentration levels less thanabout 0.25 ng/mL.
 37. The method according to claim 36 wherein saidapomorphine or pharmaceutically acceptable salt thereof is administeredto said human in an amount sufficient to produce plasma concentrationlevels in the range of about 0.02 ng/mL to about 0.25 ng/mL.